“热量限制”调控细胞毒T细胞CRAC通道促进免疫杀伤作用的机制及其免疫学标志物研究

热量限制（CR）能够显著促进健康和调节免疫功能，但机制不明、标志物缺乏限制了其临床应用。细胞毒T细胞（CTL）是关键的杀伤性免疫细胞。申请人发现CR显著促进荷瘤小鼠外周血和肿瘤组织中CTL的比例及其抗肿瘤效应，但调控机制有待深入研究。我们发现CR促进CTL的钙内流，并促进钙释放激活钙离子通道（CRAC）关键分子的表达。基于CRAC通道在调控CTL杀伤效应中的关键作用，我们推测CR可能通过CRAC通道促进CTL的杀伤作用。因此我们提出科学假说：CR通过上调CRAC通道分子表达促进CTL的钙内流，增强其杀伤作用。我们拟运用体内外模型、转录组测序和临床队列研究，阐明CR调控CTL中CRAC通道的作用和机制，并通过CTL及其表达分子等作为免疫学标志物评价CR的免疫调节功能。本项目将阐明CR调控CTL功能的分子机制和理论，促进CR免疫调节的功能评价和潜在检验标志物的研发。

Calorie restriction(CR) is a dietary intervention that can significantly promote health and regulate immune function, however, the undefined mechanism and limitation in biomarker astricts its clinical application. Cytotoxic T lymphocyte (CTL) is the key killer cell, we find that CR significantly increased the rate of CTL in peripheral blood and tumor of mice that inoculated with cancer cell. However, the mechanism under this phenomenon needs further investigation. Our preliminary data finds that CR significantly elevates calcium entry as well as the expression of Calcium Release Activated Calcium channel(CRAC) in CTL. Considering the critical roles of CRAC, a key calcium channel, in regulating CTL function, we suggest that CR might control the function of CTL via CRAC. Therefore, we hypothesize that CR elevates the expression and function of CRAC in CTL, hence enhance the killing capacity. This project will employ model in vivo and in vitro and transcriptome sequencing as well as clinical cohort study to uncover the molecular mechanism of CR promoted CTL function, and develop immunologic biomarkers of the immune modulation of CR. This study will supplement the theoretical basis of CR-regulated CTL function, and promote the development of immune assessable parameters and potent immunologic laboratory biomarker of CR.